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Eur J Cardiothorac Surg 2004;26:947-950
© 2004 Elsevier Science NL

How much heparin do we really need to go on pump? A rethink of current practices

Cork University Hospital, Cork, Ireland

Received 26 August 2003; received in revised form 1 June 2004; accepted 1 July 2004.

^* Corresponding author. Address: 10 Orby Drive, The Gallops, Leopardstown, Dublin D18, Ireland. Tel.: +353-87-2244262; fax: +353-1-2130971. (E-mail: msampca{at}msn.com).

	Abstract

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion Appendix A. Conference... References

 
Objectives: Patients undergoing myocardial revascularisation using extracorporeal circulation require heparin anticoagulation. We aimed to evaluate the effect of reducing heparin dosage on target activated clotting time (ACT) and postoperative blood loss. Methods: In a prospective randomised trial, 195 patients undergoing isolated primary CABG were randomised into four groups A, B, C, and D receiving an initial heparin dosage of 100, 200, 250 and 300iu/kg, respectively. Extra incremental heparin (50iu/kg) was added if required to achieve a target ACT of 480s before initiating cardiopulmonary bypass. Postoperative blood loss was measured from the time of heparin reversal to drain removal 24h later. Results: Target ACT was achieved in 0, 63, 68.3 and 82.4% of patients in groups A, B, C and D, respectively, after the initial dose of heparin. In group B, of those not achieving target act a single increment of heparin was sufficient to achieve target ACT in further 18.6%. The mean ACT after the initial dose in groups B, C and D was 482.9, 519 and 588s, respectively (P<0.05). Postoperative blood loss in millilitre per kilogram was directly proportional to preoperative heparin dose. Conclusions: Patients receiving lower dose of heparin has lower postoperative blood loss. Of those achieving the target ACT, group B was significantly the closest to the target ACT. A starting dose of 200iu/kg of heparin and if necessary one 50iu/kg increment achieved target ACT in 81.5% of patients. The added benefit of significant drop in postoperative blood loss is evident.

	1. Introduction

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion Appendix A. Conference... References

 
Since the advent of extracorporeal circulation, inhibition of coagulation with heparin was recognised. The heparin dose required to inhibit coagulation and the degree of anticoagulation required for cardiopulmonary bypass (CPB) has been chosen empirically based on trial and error in the early studies with supplementation based on heparin half life in the circulation. Bull [4] and associates demonstrated significant patient to patient variation in dose-response. They suggested the use of individualised dose response curve of heparin based on activated clotting time (ACT) to maintain anticoagulation in a safe range with minimal testing during CPB.

An empirical dose of 300iu/kg of heparin has been universally [1] used to inhibit coagulation for CPB to achieve an ACT [2] of greater than 480s as recommended by most non heparin coated extracorporeal circuit manufacturers.

We hypothesise that this empirical heparin dose is excessive and is associated with increased postoperative blood loss.

	2. Patients and methods

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion Appendix A. Conference... References

 
The protocol was approved by the ethical committee at Cork University Hospital and informed consents were obtained from all patients. Two hundred patients undergoing an elective isolated primary coronary artery bypass graft were recruited; all patients had only one internal thoracic artery (ITA) to the Lad and long saphenous vein to the remaining targets.

Randomisation was done by picking a sealed envelope with a group designation, into four groups A, B, C and D (control) receiving an initial heparin dose of 100, 200, 250 and 300iu/kg, respectively. Patients with history of bleeding disorders, liver disease or receiving preoperative heparin were excluded. Other exclusion criteria included low preoperative heamoglobulin <8g/dl, re-exploration for surgical bleeding, the use of Aprotinin or Transamenic acid intra operatively and morbid obesity. All patients received aspirin on the preoperative day and were restated back on it after removal of chest drains 24h later. The operating surgeon and intensive care clinician were blinded to the dose of heparin used. All data were systematically collected by one of the authors and analysed at the conclusion of the study. Heparin was given through the central venous line as a bolus after ITA harvest and before cannulation.

ACT measurement and Quality control. ACT was measured in duplicates, using Hemochron^® Response system, two minutes [3] after each heparin administration. We used an ACT of 480s as target ACT following our unit protocol which is based on the recommendation of most pump manufacturers.

We checked the temperature of the Hemochron wells once a week and used ACT checks using Electronic System Verification Tubes (manufactured by ITC corporation) for high 500, medium 300 and low 100 readings once a week.

The machine would be passed for use if the readings were within 10% of the ESV value.

If target ACT was not achieved additional heparin was given in 50iu/kg increments. The different groups were analysed for the total heparin needed to achieve the target ACT and the degree by which the target ACT was exceeded after the initial dose. For the purpose of evaluating the relation between preCPB heparin and postoperative blood loss we regrouped the patients into groups I–V based on the actual total heparin received preCPB (Tables 1 and 2). The postoperative blood loss in millilitre per kilogram was evaluated in each group from the time of heparin reversal till the chest drains were removed 24h later.

	3. Results

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion Appendix A. Conference... References

 
Complete data was collected in 195 patients. Patients demographics, mean weight, preoperative ACT and bypass time did not differ significantly (Table 1). None of the patients receiving 100iu/kg initial dose of heparin (group A) achieved target ACT (Table 3).

View larger version (61K): [in this window] [in a new window]   Fig. 1. Percentage of patients from each group requiring more heparin than the standard dose of 300iu/kg.

View larger version (66K): [in this window] [in a new window]   Fig. 2. Mean ACT after the initial dose of heparin in different groups.

View larger version (105K): [in this window] [in a new window]   Fig. 3. Mean postoperative blood loss in millilitre per kilogram of patients receiving different preCPB heparin doses.

	4. Discussion

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion Appendix A. Conference... References

 
The current practise of using 300iu/kg of heparin to achieve the target ACT to go on CPB has little evidence in the literature. The impracticality of individualised dose response curves has been recognised. Our observation that 40% of the patients receiving the standard dose of heparin will exceed the target by more than 10% before the initiation of CPB and further 20% as shown by others [5] will require extra heparin supplementations to achieve target ACT has prompted us to undertake this study.

We hypothesised that the ideal dose will need to have the following criteria

(1) High percent of patients reach the target ACT with the initial dose

(2) Low percentage of patients will exceed the target by more than 10%

(3) As few as possible increments to achieve the target ACT

We also have shown that the lower the dose of heparin the less the blood loss postoperatively.

It became apparent that a starting lower dose of heparin at 200iu/kg and one 50iu/kg increment if needed will achieve the set ACT target in 81.5% of patients and 94.45% after a second increment.

Starting with a much lower heparin doses (100iu/kg) proved impractical and time consuming since we needed more than three increments to achieve targets in a similar percentage of patients.

Using higher heparin doses will achieve the targets in comparable percentage of patients at the expense of significantly higher dose of heparin.

This higher dose of heparin is associated with significantly higher postoperative blood loss [7].

We do recognise the limitation of this study, the impact of compounding variables such as heparin resistance and anti-thrombin activity. But these variables were not preidentified and should affect the study and standard dosage equally.

We also believe that the risk of under heparinisation is cancelled out in the study design since we did neither change the desired target ACT nor any of our intra or postoperative practises. Furthermore, if heparin was needed it was given and that explains the migration of patients to different groups when we looked at the relation of preoperative total heparin dose and postoperative blood loss. We did realise that heparin dose response is not predictable. To minimise the confounding variables we used one single batch of porcine heparin 1000iu/ml (Leo labs) and was kept under constant environmental control during the study period.

Blood loss was significantly lower in patients receiving 200iu/kg of heparin compared to the other regiments.

This led us to adapt the 200iu/kg initial dose of heparin and if necessary further increments of 50iu/kg to achieve the target ACT. With this protocol we got more patients with less heparin achieving the target ACT without compromising practicality.

Other potential advantages such as blood transfusion requirement, length of ICU stay and cost need to be evaluated.

	Appendix A. Conference discussion

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion Appendix A. Conference... References

 
Dr J. Pepper (London, UK): I'm a little bit concerned that the work of Despotis and others have shown that ACT is a very, very unreliable monitor. I wondered whether you looked at thrombin/antithrombin-III levels?

Dr Shuhaibar: We haven't, actually.

Dr Pepper: But the danger is that at that level there is microthrombosis going on and the body responds by activating fibrinolysis. But you don't seem to have looked at TAT levels.

Dr Shuhaibar: No, we haven't. The reason is that there are other multifactorial reasons that will affect the overall results; however, we looked at outcome in a pure clinical sense, and none of our patients who had undergone the study had evidence to suggest microembolism or a coagulopathy after the bypass.

Dr R. El Oakley (Brunei Darussalam): Have you discussed this with a pharmacologist? And can you give us a scientific basis that explains your findings?

Dr Shuhaibar: As I just said, it's basically a clinical sense. We have to keep in mind, the initial, the standard dose, as we call it, of heparin was achieved based on historical assumptions. This study, basically, is a preliminary study to show the practical aspect of using a lower dose. However, I take your point. We are planning to do more lab based study to explain some of the features that we weren't expecting when we were looking at the different groups.

Dr El Oakley: You are proposing a slow heparinisation protocol; this may suggest that if 200 is better than 300, then a 100 will be better than 200!

Dr Shuhaibar: No. One hundred, if you want to follow the didactic sense of the word, supposedly to be better. However, we are combining a scientific approach without compromising clinical practicality. If we started with the 100, sure, we are going to reach the target ACT eventually. But when?

We have to remember that we have to wait for an ACT of about 500s. We have to wait 2min to start the ACT. So every regimen will add at least between 8 and 9min. So I don't think any cardiac surgeon in practice would like to wait 45min to get the target ACT.

However, the reason we went through the different spectrum of heparin dose is just to fine-tune what would be the dose of heparin that would be useful, reflective in less blood loss, as well as practical. And this is why we choose the 200. I mean, we can go to the (slide which shows the 250) Table 1 (in the manuscript). Initially, you will have the impression that you are reaching more target ACT after the first dose. But if we look at the increments, we can see we haven't compromised on practicality in that the same final percentage of patients reached the target ACT whether they are receiving the standard dose or the 200 international units, this dose is actually not delaying the operation. Whereas if we go to the 100, they would need at least 5 increments to reach the target ACT.

Now, if you ask me, how could you explain that? It could be heparin disassociation or the half-life of heparin broken. I cannot give you a scientific answer, and I'm not going to stand on any, but we are going to look into that.

	Footnotes

 
Presented at the joint 17th Annual Meeting of the European Association for Cardio-thoracic Surgery and the 11th Annual Meeting of the European Society of Thoracic Surgeons, Vienna, Austria, October 12–15, 2003.

	References

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion Appendix A. Conference... References

 

1. Doty DB, Knot HW, Hoyt JI, Koepke JA. Heparin dose for accurate anticoagulation in cardiac surgery. J Cardiovasc Surg 1979;20:597-604.[Medline]
2. Hattersly PG. Activated coagulation time of whole blood. J Am Med Assoc 1966:136-146.
3. Coleman ET, Hargrove M, Singh HP, Aherne T. Estimation of minimum heparin circulating time for activated clotting time determination. J Extra Corp Tech 1994;26:61-63.
4. Bull BS, Korpelman RA, Huse WM, Briggs BD. Heparin therapy during extracorporeal circulation. II. The use of a dose-response curve to individualize heparin and protamine dosage. J Thorac Cardiovasc Surg 1975;69(5):685-689.[Abstract]
5. Metz S, Keats AS. Low activated clotting time does not increase postoperative bleeding. Ann Thorac Surg 1990;49:440-444.[Abstract]
6. Vertrees RA, Engelman RM, Breyer RH, Johnson J, Auvil J, Rousou JA. Protamine-induced anticoagulation following coronary bypass. Proc Am Acad Cardiovasc Perf 1985;6:84-88.
7. Despotis GJ, Joist JH, Hogue Jr. CW, Alsoufiev A, Kater K, Goodnough LT, Santoro SA, Spitznagel E, Rosenblum M, Lappas DG. The impact of heparin concentration and activated clotting time monitoring on blood conservation: a prospective, randomized evaluation in patients undergoing cardiac operation. J Thorac Cardiovasc Surg 1995;110(1):46-54.[Abstract/Free Full Text]

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): T. Aherne Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shuhaibar, M.N. Articles by Aherne, T. Search for Related Content PubMed PubMed Citation Articles by Shuhaibar, M.N. Articles by Aherne, T. Related Collections Cardiac - other Coronary disease Extracorporeal circulation